This invention relates to 5-arylsulfonyl-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazine-6-amines and related compounds. The compounds are selective inhibitors of phosphodiesterase type 4 (PDE4) and the production of tumor necrosins factor (TNF), and as such are useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia, and AIDS.
This invention also relates to a method of using such compounds in the treatment of the foregoing diseases in mammals, especially humans, and to pharmaceutical compositions containing such compounds.
Since the recognition that cyclic adenosine tri-phosphate (cAMP) is an intracellular second messenger, inhibition of the phosphodiesterases has been a target for modulation and, accordingly, therapeutic intervention in a range of disease processes. More recently, distinct classes of PDE have been recognized and their selective inhibition has led to improved drug therapy. More particularly, it has been recognized that inhibition of PDE4 can lead to inhibition of inflammatory mediator release and airway smooth muscle relaxation. Thus, compounds that inhibit PDE4, but which have poor activity against other PDE types, would inhibit the release of inflammatory mediators and relax airway smooth muscle without causing cardiovascular effects or antiplatelet effects.
Recent molecular cloning has revealed a complexity and diversity of PDE4 enzymes. It is now known that there are four distinct PDE4 isozymes (A, B, C and D), each encoded for by a separate gene. Kinetic studies of human recombinant materials suggest that these four isozymes may differ in their Km""s and Vmax""s for hydrolysis of cAMP. Analysis of tissue distribution of PDE4 mRNAs suggests that each isozyme may be localized in a cell-specific pattern.
The present invention relates to a compound of the formula 
and the pharmaceutically acceptable salts thereof; wherein
a is 1, 2, 3 or 4;
X is CH or N;
R1 and R2 are each independently selected from hydrogen, (C1-C6)alkyl, cyano, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C3-C7)cycloalkyl, (C6-C10)aryl and a saturated or unsaturated, cyclic or bicyclic (C2-C9)heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR6 wherein R6 is hydrogen or (C1-C6)alkyl;
R3 and R4 are each independently selected from hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, hydroxy, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C3-C7)cycloalkyl, (C3-C7)cycloalkoxy, (C6-C10)aryl or a saturated or unsaturated, cyclic or bicyclic (C2-C9)heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR6 wherein R6 is defined as above;
or R1 and R2 may be taken together with the carbons to which they are attached to form a compound of formula II 
wherein
a, X, R3 and R4 are as defined above;
b is 1,2,3 or 4; and
R5 is hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, hydroxy, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C3-C7)cycloalkyl, (C3-C7)cycloalkoxy, (C6-C10)aryl or a saturated or unsaturated, cyclic or bicyclic (C2-C9)heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR6 wherein R6 is defined as above.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9ca saturated or unsaturated, cyclic or bicyclic (C2-C9) heterocyclic group containing as the heteroatom one to four of the group consisting of oxygen, sulfur, nitrogen or NR6 wherein R6 is as defined abovexe2x80x9d, as used herein, unless otherwise indicated, includes but is not limited to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyi, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl and benzoxazinyl.
The term xe2x80x9chaloxe2x80x9d, as defined herein, includes fluoro, chloro, bromo or iodo.
Preferred compounds of formula I include those wherein X is nitrogen.
Other preferred compounds of formula I include those wherein R1 is hydrogen, (C1-C6)alkyl, amino, cycloalkyl or (C6-C10)aryl.
Other preferred compounds of formula I include those wherein R2 is hydrogen, (C1-C6)alkyl, amino, cycloalkyl or (C6-C10)aryl.
Other preferred compounds of formula I include those wherein R3 is hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, amino, hydroxy, cycloalkyl or (C6-C10)aryl.
Other preferred compounds of formula I include those wherein R4 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, amino, hydroxy, cycloalkyl or (C6-C10)aryl.
Other preferred compounds of formula II include those wherein R5 is hydrogen, halo, (C1-C6)alkyl, (C1-C6)alkoxy, cyano, amino, hydroxy, cycloalkyl or (C6-C10)aryl.
More preferred compounds of formula I include those wherein X is nitrogen; R1 is hydrogen, (C1-C6)alkyl, amino, cycloalkyl or (C6-C10)aryl; R2 is hydrogen, (C-C6)alkyl, amino, cycloalkyl or (C6-C10)aryl; R3 is hydrogen, halo, (C1-C6)alkyl, cyano, amino, hydroxy, cycloalkyl or (C6-C10)aryl; and R4 is hydrogen, (C1-C6)alkyl, amino, hydroxy, cycloalkyl or (C6-C10)aryl.
More preferred compounds of formula II include those wherein X is nitrogen; R3 is hydrogen, halo, (C1-C6)alkyl, cyano, amino, hydroxy, cycloalkyl or (C6-C10)aryl; R4 is hydrogen, (C1-C6)alkyl, amino, hydroxy, cycloalkyl or (C6-C10)aryl and R5 is hydrogen, (C1-C6)alkyl, cyano, amino, hydroxy, cycloalkyl or (C6-C10)aryl.
Specific preferred compounds of formula I include the following:
5-[(4-methylphenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-methylphenyl)sulfonyl]-[1,2,4]triazolo[4xe2x80x2,3xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-ethylphenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-isopropylphenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-propylphenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-methoxyphenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-ethylphenyl)sulfonyl]-[1,2,4]triazolo[4xe2x80x2,3xe2x80x2:1,6]pyrido[2,3-b]quinoxaline-4-amino;
5-[(4-fluorophenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-chlorophenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(3-methoxyphenyl)sulfonyl]-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine;
5-[(4-methoxyphenyl)sulfonyl]-[1,2,4]triazolo[4xe2x80x2,3xe2x80x2:1,6]pyrido[2,3-b]pyrazin-6-amine; and
5-[(4-methoxyphenyl)sulfonyl]-[1,2,4]triazolo[4xe2x80x2,3xe2x80x2:1,6]pyrido[2,3-b]quinoxaline-4-amine;
The present invention also relates to a pharmaceutical composition for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, effective in such treatment and a pharmaceutically acceptable carrier.
The present invention also relates to a method for the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, Crohn""s disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS in a mammal, including a human, comprising administering to said mammal an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, effective in such treatment.
The following reaction Schemes illustrate the preparation of compounds of the present invention. Unless otherwise indicated a, b, X, R1, R2, R3, R4 and R5 in the reaction Schemes and the discussion that follow are defined as above. 
In reaction 1 of Scheme 1, the benzenesulfonyl chloride compound of formula III is converted to the corresponding cyano compound of formula IV by in situ reduction of III to the corresponding sulfinate salt followed by reaction with a haloacetonitrile, preferably bromoacetonitrile. The reaction mixture so formed is heated at a temperature between about 50xc2x0 C. to about 70xc2x0 C, preferably about 60xc2x0 C., for a time period between about 1 hour to about 3 hours, preferably about 2 hours.
In reaction 2 of Scheme 1, the compound of formula IV is converted to the corresponding pyrazineacetonitrile compound of formula V by reacting IV with a 2,3-dichloropyrazine compound of formula 
in the presence of potassium carbonate and a polar aprotic solvent, such as dimethylformamide. The reaction mixture is heated at a temperature between about 70xc2x0 C. to about 90xc2x0 C., preferably about 80xc2x0 C., for a time period between about 6 hours to about 8 hours, preferably about 7 hours.
In reaction 3 of Scheme 1, the pyrazineacetonitrile compound of formula V is converted to the corresponding 5-arylsulfonyl-imidazo[1xe2x80x2,2xe2x80x2:1,6]pyrido[2,3-6]pyrazine-6-amine compound of formula I by reacting V with a 1-methylimidazole, when X is CH, or a 1-methyl-1,2,4-triazole, when X is N, in a polar aprotic solvent, such as dimethylformamide. The reaction mixture so formed is heated to a temperature of about 140xc2x0 C. to about 180xc2x0 C., preferably 160xc2x0 C., for a time period between about 1 hour to about 8 hours, preferably about 6 hours.
In reaction 1 of Scheme 2, the compound of formula IV is converted to the corresponding benzopyrazineacetonitrile compound of formula VI by reacting IV with a dichlorobenzopyrazine compound of the formula 
in the presence of potassium carbonate and a polar apotic solvent, such as dimethylformamide. The reaction mixture is heated at a temperature between about 70xc2x0 C. to about 90xc2x0 C., preferably about 80xc2x0 C., for a time period between about 6 hours to about 8 hours, preferably about 7 hours.
In reaction 2 of Scheme 2, the compound of formula VI is converted to the corresponding compound of formula II according to the procedure described above in reaction 3 of Scheme 1.
The compounds of formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to humans or animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is readily obtained. The desired acid addition salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid. Pharmaceutically acceptable salts of amino groups include hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. Cationic salts of the compounds of formula I are similarly prepared except through reaction of a carboxy group with an appropriate cationic salt reagent such as sodium, potassium, calcium, magnesium, ammonium, N,Nxe2x80x2-dibenzyiethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
For administration to humans in the curative or prophylactic treatment of inflammatory diseases, oral dosages of a compound of formula I or a pharmaceutically acceptable salt thereof (the active compounds) are generally in the range of 0.1 to 1000 mg daily, in single or divided doses, for an average adult patient (70 kg). The active compounds can be administered in single or divided doses. Individual tablets or capsules should generally contain from 0.1 to 100 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier. Dosages for intravenous administration are typically within the range of 0.1 to 10 mg per single dose as required. For intranasal or inhaler administration, the dosage is generally formulated as a 0.1 to 1% (w/v) solution. In practice the physician will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case but there can, of course, be individual instances where higher or lower dosage ranges are merited, and all such dosages are within the scope of this invention.
For human use, the active compounds of the present invention can be administered alone, but will generally be administered in an admixture with a pharmaceutical diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. They may be injected parenterally; for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances; for example, enough salts or glucose to make the solution isotonic.
Additionally, the active compounds may be administered topically when treating inflammatory conditions of the skin and this may be done by way of creams, jellies, gels, pastes, and ointments, in accordance with standard pharmaceutical practice.
The therapeutic compounds may also be administered to a mammal other than a human. The dosage to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds may be administered to animals in the form of a capsule, bolus, tablet or liquid drench. The therapeutic compounds may also be administered to animals by injection or as an implant. Such formulations are prepared in a conventional manner in accordance with standard veterinary practice. As an alternative the therapeutic compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
The ability of the compounds of formula I or the pharmaceutically acceptable salts thereof to inhibit PDE4 may be determined by the following assay.
Preparation of Test Compounds
Compounds are dissolved in dimethyl sulfoxide at a concentration of 1xc3x9710xe2x88x922 M, or to a desired higher concentration if solubility is an issue then diluted 1:25 in water (4xc3x9710xe2x88x924 M compound, 4% DMSO). Further serial dilutions are made in 4% dimethyl sulfoxide to achieve desired concentrations. Final dimethyl sulfoxide concentration in assay is 1%.
In duplicate, the following are added in order to a scintillation vial (all concentrations are given as final concentrations in vial).
25 xcexcl compound of dimethyl sulfoxide (1%, for blank)
25 xcexcl [3H] cAMP-containing assay buffer (1 xcexcM [3H] cAMP, 50 mM Tris, 10 mM MgCl2, pH 7.5)
25 xcexcl 5xe2x80x2-nucleotidase (0.001 unit) (Sigma #N5880)
25 xcexcl PDE4 isozyme (1/1200-1/2400 dilution in Prep #1)
The reaction vials are shaken and placed in a water bath (3.7xc2x0 C.) for 30 minutes, at which time the reaction is stopped by adding 1 ml Dowex 1xc3x978 resin, chloride form (1:3 slurry in distilled water). Three ml Ready Safte scintillation fluid are added directly to each vial. Mix each vial well and count radioactivity after resin has settled (approx. 4 hours at room temperature).
Data Calculation and Interpretation
Percent inhibition is determined by the formula:             %      ⁢              xe2x80x83            ⁢      inh        =          1      -                                                                  avg                .                                  xe2x80x83                                ⁢                cpm                            ⁢                              xe2x80x83                            ⁢                              (                                  test                  ⁢                                      xe2x80x83                                    ⁢                  compound                                )                                      -                                          avg                .                                  xe2x80x83                                ⁢                cpm                            ⁢                              xe2x80x83                            ⁢                              (                blank                )                                                                        avg              .                              xe2x80x83                            ⁢              cpm                        ⁢                          xe2x80x83                        ⁢                          (                                                control                  ⁢                                      xe2x80x83                                    ⁢                                      (                                          no                      ⁢                                              xe2x80x83                                            ⁢                      compound                                        )                                                  -                                                      avg                    .                                          xe2x80x83                                        ⁢                    cpm                                    ⁢                                      xe2x80x83                                    ⁢                                      (                    blank                    )                                                                                      xc3x97        100              ⁢      xe2x80x83  
IC50 is defined as that concentration of compound which inhibits 50% of radioactivity, and is determined by Microsoft Excel or other appropriate software.
The present invention is illustrated by the following examples, but is not limited to the details thereof.
In a 125 mL, three-necked flask fiited with thermometer, addition funnel, and glass stopper was placed 11.5 grams (91.2 mmol) of sodium sulfite, 8.32 grams (97.7 mmol) of sodium bicarbonate, and 50 mL of water. After heating the mixture to 75-80xc2x0 C., 10.0 grams (48.9 mmol) of 4-ethylbenzenesulfonyl chloride was added dropwise over 0.5 hours. When the addition was complete, heating was continued for 3 hours at which time a white precipitate formed. The suspension was cooled to room temperature and allowed to stir for 16 hours. The precipitate was collected by filtration, washed with cold water, combined with a second crop from the filtrate, and dried under high vaccum to give 13.9 grams ( greater than 100% yield) of crude sodium 4-ethylbenzenesulfinate.
In a small Parr bottle was placed the salt above, 3.09 mL (5.33 grams, 44.9 mmol) of bromoacetonitrile, and 0.488 grams of aliquat(trademark)-336. The contents were agitated on a Vortex-2 Genie(trademark) for 5 minutes using a spatula to maintain homogeneity. The bottle was transferred to an oil bath and heated for 2 hours at 60xc2x0 C., as the mixture softened, turned pink-orange, and then hardened. The solid was extracted with 250 mL of ethyl acetate, filtered, and evaporated to a solid. Trituration in methylene chloride gave 5.61 grams (55% yield) of the title compound as an off-white solid. Melting Point: 120-121xc2x0 C. Anal. Calcd for C10H11NO2S: C, 54.40; H, 5.30; N, 6.69. Found: C, 57.29; H, 5.39; N, 6.6.1.
The compounds of Preparations 2-4 were prepared according to the procedure of Preparation 1 substituting the indicated sulfonyl chloride for 4-ethylbenzenesulfonyl chloride.
A mixture of 6.38 grams (32.7 mmol) of (4-methylbenzenesulfonyl)acetonitrile (for preparation, see: Bram, G. et al., Synthesis, 1987, 56), 4.87 grams (32.7 mmol) of 2,3-dichloropyrazine, 4.97 grams (36.0 mmol) of potassium carbonate, and 10 mL of dimethylformamide was heated for 7 hours at 80xc2x0 C. The solvent was removed by vaccum distillation, and the residue was diluted with 100 mL of aqueous 1 N hydrochloric acid solution and extracted with ethyl acetate (1xc3x97150 mL, 1xc3x97100 mL). The combined extracts were washed with brine (1xc3x97100 mL), dried (magnesium sulfate) and evaporated to give 8.9 grams of a dark oil. Purification by flash chromatography using a 30-50% ethyl acetate-hexane eluant gave 2.35 grams of solid which was triturated in ether to afford 2.20 grams (20% yield) of the title compound as a white solid. Melting Point: 148-151xc2x0 C. (lit. 126xc2x0 C. (Litvinenko, S. V. et al., Chem. Heterocycl. Compd. (Eng. Transl.), 1992, 28, 93)). Anal. Calcd for C13H10N3O2CIS: C, 50.74; H, 3.28; N, 13.65. Found: C, 50.45; H, 3.53; N, 13.77.
The compounds of Preparations 6-9 were prepared according to the procedure of Preparation 5 substituting the indicated substrate for (4-methylbenzenesulfonyl)acetonitrile.
The title compound was prepared as a tan powder, melting point 208-211xc2x0 C., according to the procedure of Preparation 5 substituting the compound of Preparation 1 for (4-methylbenzesulfonyl)acetonitrile and substituting 2,3-dichlorquinazoline for 2,3-dichloropyrazine. Calcd for C18H14N3O2SCI: C, 58.14 H, 3.79; N, 11.30. Found: C, 58.15; H, 3.59; N, 11.32.